Genital Herpes Simplex Virus Type Research Articles

Oral Self-Nanoemulsifying System Containing Ionic Liquid of BX795 Is Effective against Genital HSV-2 Infection in Mice.

BX795 is an emerging drug candidate that has shown a lot of promise as a next-generation non-nucleoside antiviral agent for the topical treatment of herpes simplex virus type-1 (HSV-1) and herpes simplex virus type-2 (HSV-2) infections. Our studies indicated that BX795 has limited oral bioavailability, which could be attributed to its low and pH-dependent solubility. Lipid-based formulations such as self-nanoemulsifying systems (SNESs) can improve the solubility and oral bioavailability of BX795, but the poor lipid solubility of BX795 further limits the development of SNES. To improve the loading of BX795 into SNES, we evaluated the ability of various bulky and biocompatible anions to transform BX795 into an ionic liquid (IL) with higher lipid solubility. Our studies showed that sodium lauryl sulfate and docusate sodium were able to transform BX795 into IL. Compared to pure BX795, the developed BX795 ILs showed differential in vitro cytocompatibility to HeLa cells but exhibited similar in vitro antiviral activity against HSV-2. Interestingly, BX795 docusate (BX795-Doc), an IL of BX795 with ∼135-fold higher lipid solubility than pure BX795, could be successfully incorporated into an SNES, and the developed BX795-Doc-SNES could readily form nanoemulsions of size ≤200 nm irrespective of the pH of the buffer used for dilution. Our in vitro studies showed that BX795-Doc-SNES retained the inherent antiviral activity against HSV-2 and showed similar in vitro cytocompatibility, indicating the availability of BX795 from the SNES in vitro. Finally, orally delivered SNES containing BX795-Doc showed a significant reduction in HSV-2 infection in mice compared to the untreated control. Thus, the transformation of BX795 into IL and the subsequent incorporation of the BX795 IL into the SNES are an effective strategy to improve oral therapy of genital herpes infection.

Natural Killer Cell-Derived Interferon-γ Regulates Macrophage-Mediated Immunopathology During Viral Infection.

Regulation of immune responses during viral infection is critical to preventing the development immunopathology that impairs host survival. Natural killer (NK) cells are well known for their antiviral functions that promote viral clearance; however, their roles in limiting immune-mediated pathology are still unclear. Using a mouse model for genital herpes simplex virus type 2 infection, we find that NK cell-derived interferon-γ directly counteracts interleukin-6-mediated matrix metalloproteases (MMPs) activity in macrophages to limit MMP-mediated tissue damage. Our findings uncover a key immunoregulatory function of NK cells during host-pathogen interactions that highlight the potential of NK cell therapy for treatment of severe viral infections.

Genital Herpes Simplex Virus Type 2 Suppression With Valacyclovir Is Not Associated With Changes in Nugent Score or Absolute Abundance of Key Vaginal Bacteria.

In women, genital herpes simplex virus type 2 (HSV-2) infection is associated with increased risk for recurrent bacterial vaginosis (BV), but causal relationships are unclear. Women with a self-reported history of BV and HSV-2 seropositivity self-collected vaginal and anogenital swabs for 2 nonconsecutive 28-day periods, in the absence or presence of valacyclovir suppressive therapy (500 mg daily). HSV polymerase chain reaction was performed on anogenital swabs; vaginal swabs were used for assessment of BV by Nugent score and quantification of vaginal microbiota. Days with BV, defined by Nugent score ≥7, were compared during the observational period and valacyclovir treatment. Forty-one women collected swabs for a median of 28 days (range, 20-32 days) each study period. The HSV-2 shedding rate decreased from 109 of 1126 days (9.7%) presuppression to 6 of 1125 days (0.05%) during valacyclovir (rate ratio [RR], 0.06 [95% confidence interval {CI}, .02-.13]). BV occurred on 343 of 1103 days (31.1%) during observation and 302 of 1091 days (27.7%) during valacyclovir (RR, 0.90 [95% CI, .68-1.20]). The median per-person Nugent score was 3.8 during observation and 4.0 during valacyclovir. Average log10 concentrations of vaginal bacterial species did not change significantly during valacyclovir treatment. Short-term HSV-2 suppression with valacyclovir did not significantly affect the Nugent score or the vaginal microbiome despite potent suppression of HSV-2 shedding.

Superior antiviral activity of IFNβ in genital HSV-1 infection.

Type I interferons (IFNs) present the first line of defense against viral infections, providing antiviral, immunomodulatory and antiproliferative effects. The type I IFN family contains 12 IFNα subtypes and IFNβ, and although they share the same receptor, they are classified as non-redundant, capable to induce a variety of different IFN-stimulated genes. However, the biological impact of individual subtypes remains controversial. Recent data propose a subtype-specificity of type I IFNs revealing unique effector functions for different viruses and thus expanding the implications for IFNα-based antiviral immunotherapies. Despite extensive research, drug-resistant infections with herpes simplex virus type 1 (HSV-1), which is the common agent of recurrent orogenital lesions, are still lacking a protective or curing therapeutic. However, due to the risk of generalized infections in immunocompromised hosts as well as the increasing incidence of resistance to conventional antiherpetic agents, HSV infections raise major health concerns. Based on their pleiotropic effector functions, the application of type I IFNs represents a promising approach to inhibit HSV-1 replication, to improve host immunity and to further elucidate their qualitative differences. Here, selective IFNα subtypes and IFNβ were evaluated for their therapeutic potential in genital HSV-1 infections. Respective in vivo studies in mice revealed subtype-specific differences in the reduction of local viral loads. IFNβ had the strongest antiviral efficacy against genital HSV-1 infection in mice, whereas IFNα1, IFNα4, and IFNα11 had no impact on viral loads. Based on flow cytometric analyses of underlying immune responses at local and peripheral sites, these differences could be further assigned to specific modulations of the antiviral immunity early during HSV-1 infection. IFNβ led to enhanced systemic cytokine secretion and elevated cytotoxic responses, which negatively correlated with viral loads in the vaginal tract. These data provide further insights into the diversity of type I IFN effector functions and their impact on the immunological control of HSV-1 infections.

Molecular Epidemiology and Risk Factors of Herpes Simplex Virus Type 2 in Pregnant Women

Background: Herpes simplex virus type 2 (HSV-2) infection is the main cause of genital and neonatal herpes infections. It has considerable public health importance among women as the virus may lead to adverse outcomes in pregnancy and neonatal infection. This study determines the molecular epidemiology and risk factors of HSV-2 infection among pregnant women. Methods: In this cross-sectional study, all pregnant women admitted to three university hospitals for natural birth and Caesarean sections were enrolled. HSV detection and typing were carried out based on PCR and reverse dot blotting method, respectively. ANOVA and bivariate correlations were used to analyze the data. Results: In this study, the prevalence of genital herpes infection was 5.7%. A significant positive correlation was found between age group < 25 years and HSV-2 shedding (P = 0.026). Twelve participants (60%) with HSV-2 shedding were younger than 25. A significant correlation was found between the presence of genital lesion and HSV-2 (? = 0.02). Among participants with HSV-2 infection, the use of condom was low. Neonatal complications were not seen in newborns from mothers with HSV-2 shedding. Conclusion: PCR assay may help in promoting early diagnosis and more effective treatment for patients. Also, it shortens hospital stay and enhances patients’ condition. HSV-2 transmission is rapid following the onset of sexual activity and likely to result in the significant prevalence of genital disease.

Severe diabetic ketoacidosis triggered by concomitant central nervous system and genital Herpes Simplex Virus type 2 infection.

Severe diabetic ketoacidosis triggered by concomitant central nervous system and genital Herpes Simplex Virus type 2 infection.

Immunoregulatory Functions of Interferons During Genital HSV-2 Infection.

Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent sexually transmitted infections that disproportionately impacts women worldwide. Currently, there are no vaccines or curative treatments, resulting in life-long infection. The mucosal environment of the female reproductive tract (FRT) is home to a complex array of local immune defenses that must be carefully coordinated to protect against genital HSV-2 infection, while preventing excessive inflammation to prevent disease symptoms. Crucial to the defense against HSV-2 infection in the FRT are three classes of highly related and integrated cytokines, type I, II, and III interferons (IFN). These three classes of cytokines control HSV-2 infection and reduce tissue damage through a combination of directly inhibiting viral replication, as well as regulating the function of resident immune cells. In this review, we will examine how interferons are induced and their critical role in how they shape the local immune response to HSV-2 infection in the FRT.

Ovariectomized mice and postmenopausal women exhibit analogous loss of genital epithelial integrity.

ABSTRACT Roughly half of all postmenopausal women are affected by the genitourinary syndrome of menopause (GSM). Symptoms of GSM, including vaginal irritation and dyspareunia, occur as reduced estrogen (E) production elicits loss of elasticity and other changes in genital tract tissue. While the use of the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) likewise lowers serum E concentrations in reproductive age women and is associated with decreased genital levels of the cell-cell adhesion molecules desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and impaired genital epithelial barrier function, the relevance of these findings to women in menopause is uncertain. Exploring the impact of menopause on genital epithelial integrity herein, we detected significantly lower levels of DSG1 and DSC1 in ectocervical tissue from menopausal and postmenopausal vs premenopausal women. Using ovariectomized (OVX) mice as a menopause model, we comparably saw significantly lower vaginal tissue levels of DSG1 and DSC1 in OVX mice vs. mice in estrus. Compared to estrus-stage mice and E-treated OVX mice, DMPA-treated ovary-intact mice and OVX mice also exhibited significantly reduced genital epithelial barrier function, greater susceptibility to genital herpes simplex virus type 2 infection, and delayed clearance of genital Chlamydia trachomatis infection. Current studies thus identify analogous loss of genital epithelial integrity in OVX mice and menopausal and postmenopausal women. By showing that loss of genital epithelial integrity is associated with increased mouse susceptibility to bacterial and viral pathogens, our findings also prioritize the need to resolve if reduced genital epithelial integrity in postmenopausal women is a significant risk factor for genital infection.

Reduced Desmosomal Cadherin Levels in Genital Epithelium of Postmenopausal Women Also Develop in Ovariectomized Mice with Increased Susceptibility to Viral and Bacterial Genital Pathogens

Background: The genitourinary syndrome of menopause affects about half of all women in menopause and includes symptoms of vaginal burning, dyspareunia, and urinary urgency. These symptoms stem from lower serum estrogen levels in postmenopausal women that cause reduced tissue elasticity and other genital tract changes. While the hypoestrogenemia induced in reproductive age women using the progestin-only contraceptive depot-medroxyprogesterone acetate (DMPA) decreases genital levels of the cell-cell adhesion molecules desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and impairs genital epithelial barrier function, relevance of these findings to postmenopausal women is uncertain. Methods: We compared ectocervical DSG1 and DSC1 levels in premenopausal vs. postmenopausal women. Using ovariectomized mice to model the hypoestrogenic state in postmenopausal women, we explored effects of reduced ovarian function on genital epithelial integrity barrier function and genital pathogen susceptibility. Findings: Compared to premenopausal women, ectocervical tissue from women in menopause had significantly lower levels of DSG1 and DSC1. Likewise, Dsg1 and Dsc1 levels were significantly reduced in OVX mice vs. estrus-stage mice. Consistent with these data, DMPA-treated and OVX mice displayed significant compromise of genital epithelial barrier function and compared to estrus-stage mice or OVX mice treated with estrogen, were more susceptible to genital herpes simplex virus type 2 infection and less effectively cleared genital Chlamydia trachomatis infection. Interpretation: Our studies identify analogously reduced genital epithelial integrity in postmenopausal women and OVX mice and indicate that reduced ovarian function alters host response to bacterial and viral pathogens. Our results also spotlight the need to resolve if weakened genital epithelial integrity in postmenopausal women represents an important risk factor for genital infection. Funding Statement: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD094634) and Stanford University School of Medicine. Declaration of Interests: Authors have no conflicts of interest to declare. Ethics Approval Statement: Prior to induction, all proposed mice studies were approved by the Stanford University Institutional Animal Care and Use Committee.

Time Trends in First-Episode Genital Herpes Simplex Virus Infections in an Urban Sexually Transmitted Disease Clinic.

Genital herpes simplex virus type 1 (HSV-1) has emerged as the leading cause of first-episode genital herpes among specific populations in the United States, such as adolescents, young adult women, and men who have sex with men (MSM). We examined trends in the etiology of first-episode genital herpes diagnoses over time in a sexually transmitted disease (STD) clinic population. Using an electronic database, we identified persons diagnosed as having first-episode genital herpes at Public Health - Seattle & King County STD Clinic from 1993 to 2014 and compared risk factors for genital HSV-1 versus herpes simplex virus type 2 (HSV-2) infection. Of 52,030 patients with genital ulcers, 3065 (6.15%) had first-episode genital herpes infection: 1022 (33.3%) with HSV-1 and 2043 (67.7%) with HSV-2. Overall, 1154 (37.7%) were women, the median age was 28 years (interquartile range, 24-36 years), 1875 (61.2%) patients were white, and 353 (11.5%) were MSM. The number of patients diagnosed as having first-episode genital HSV-2 declined on average by 5.5 persons per year, from 208 in 1993 to 35 in 2014 (change of -5.6 per year; 95% confidence interval [CI], -6.9 to -4.1), whereas HSV-1 diagnoses remained stable at approximately 50 per year (change of 0.2; 95% CI, -0.4 to 0.9). In a multivariate model, persons diagnosed as having first-episode genital HSV-1 rather than genital HSV-2 infection were more likely to be younger (age <30 years [relative risk {RR}, 1.38; 95% CI, 1.22-1.55]), white (RR, 3.16; 95% CI, 2.57-3.88), and MSM (RR, 1.50; 95% CI, 1.31-1.71). We observed a significant decrease in the frequency of first-episode genital HSV-2 and a stable number of first-episode genital HSV-1 infections in a STD clinic over the last 2 decades.

Depot-medroxyprogesterone acetate reduces genital cell–cell adhesion molecule expression and increases genital herpes simplex virus type 2 infection susceptibility in a dose-dependent fashion

ObjectiveAnalyzing ectocervical biopsy tissue from women before and after they initiated use of depot-medroxyprogesterone acetate (DMPA), we previously reported this progestin reduces levels of the cell–cell adhesion molecule (CCAM) desmoglein-1 and increases genital mucosal permeability. We likewise saw treating mice with 1.0 mg of DMPA reduced vaginal CCAM expression and increased genital pathogen susceptibility. Herein, we used dose–response studies to delimit DMPA doses and serum MPA levels in mice associated with impaired genital mucosal barrier function and enhanced susceptibility to low-dose herpes simplex virus type 2 (HSV-2) infection. Study designWe compared genital CCAM expression, genital mucosal permeability, and susceptibility to genital inoculation with 103 plaque-forming units of HSV-2 among mice in estrus vs. after treatment with 0.01 mg, 0.1 mg, 0.3 mg, or 1.0 mg of DMPA. ResultsCompared to mice in estrus, DMPA treatment in a dose-dependent fashion significantly reduced desmoglein 1α (Dsg1a) and desmocollin-1 (Dsc1) gene expression, reduced DSG1 protein levels, and increased genital mucosal permeability to a low molecular weight molecule. While no mice infected with HSV-2 in estrus died, we respectively saw 50% and 100% mortality in mice administered 0.1 mg or 0.3 mg of DMPA. At time of infection, mean serum MPA levels in mice administered the 0.1 mg or 0.3 mg doses were 3.8 nM and 13.0 nM respectively (values comparable to trough and peak MPA serum levels in women using DMPA). ConclusionsMice with pharmacologically relevant serum MPA concentrations display significant changes in genital CCAM expression, genital mucosal barrier function, and HSV-2 susceptibility.

Development of disease and immunity at the genital epithelium following intrarectal inoculation of male guinea pigs with herpes simplex virus type 2

Most analyses of genital immunity to herpes simplex virus type 2 (HSV-2) have been performed in females, consequently immune protection of the male genital epithelium is incompletely understood. We developed a model of male genital HSV-2 infection resulting from intrarectal inoculation of guinea pigs. Vesicular lesions developed transiently on the perineum and foreskin concurrent with acute virus shedding. Virus shedding and recurrent genital lesions were also detected after establishment of a latent infection. Analysis of perineum and foreskin RNA detected transcripts for IFNγ, proinflammatory and regulatory cytokines, and for genes involved in migration and regulation of leukocytes. HSV-specific T cells were detected in lymphoid and genital tissues after resolution of the primary infection whereas virus-specific antibody secreting cells were detected only in lymphoid tissue. Taken together, the ability to quantify pathogenesis and local immunity in this guinea pig model represent an important advance towards understanding immunity to HSV-2 in males.

Effects of Different Doses of GEN-003, a Therapeutic Vaccine for Genital Herpes Simplex Virus-2, on Viral Shedding and Lesions: Results of a Randomized Placebo-Controlled Trial.

GEN-003 is a candidate therapeutic vaccine for genital herpes simplex virus type 2 (HSV-2). We compared virologic and clinical impact of varying GEN-003 doses. Adults with symptomatic HSV-2 received placebo or GEN-003 (30 or 60 µg antigen with 25, 50, or 75 µg adjuvant). Viral shedding and lesion rates before vaccination were compared with those measured immediately after vaccination, then at weeks 29-33 and 53-57 after last dose. Compared with baseline shedding rates, the rate ratios for viral shedding immediately after treatment were as follows: 0.82 (95% confidence interval [CI], 0.49-1.36), 30 µg antigen/25 µg adjuvant (30/25) dose; 0.64 (95% CI, 0.45-0.92), 30/50 dose; 0.63 (95% CI, 0.37-1.10), 30/75 dose; 0.56 (95% CI, 0.36-0.88), 60/25 dose; 0.58 (95% CI, 0.38-0.89), 60/50 dose; 0.45 (95% CI, 0.16-0.79), 60/75 dose; and 0.98 (95% CI, 0.76-1.26), placebo. Lesion rate reductions by GEN-003 ranged from 31% to 69%, but lesion rates also decreased among placebo recipients (62%). Reductions in shedding and lesion rate were durable for 12 months for the 60 µg antigen plus 50 or 75 µg adjuvant groups. No serious adverse events occurred with vaccination. The most efficacious vaccine combinations for GEN-003 were the 60 µg/50 µg and 60 µg/75 µg doses.

Genome-Wide Surveillance of Genital Herpes Simplex Virus Type 1 From Multiple Anatomic Sites Over Time.

Here we present genomic and in vitro analyses of temporally separated episodes of herpes simplex virus type 1 (HSV-1) shedding by an HSV-1–seropositive and human immunodeficiency virus (HIV)/HSV-2–seronegative individual who has frequent recurrences of genital HSV-1. Using oligonucleotide enrichment, we compared viral genomes from uncultured swab specimens collected on different days and from distinct genital sites. We found that viral genomes from 7 swab specimens and 3 cultured specimens collected over a 4-month period from the same individual were 98.5% identical. We observed a >2-fold difference in the number of minority variants between swab specimens from lesions, swab specimens from nonlesion sites, and cultured specimens. This virus appeared distinct in its phylogenetic relationship to other strains, and it contained novel coding variations in 21 viral proteins. This included a truncation in the UL11 tegument protein, which is involved in viral egress and spread. Normal immune responses were identified, suggesting that unique viral genomic features may contribute to the recurrent genital infection that this participant experiences.

Exogenous oestrogen inhibits genital transmission of cell-associated HIV-1 in DMPA-treated humanized mice.

IntroductionHIV affects more women than any other life‐threatening infectious agent, and most infections are sexually transmitted. HIV must breach the female genital tract mucosal barrier to establish systemic infection, and clinical studies indicate virus more easily evades this barrier in women using depot‐medroxyprogesterone acetate (DMPA) and other injectable progestins for contraception. Identifying a potential mechanism for this association, we learned DMPA promotes susceptibility of wild‐type mice to genital herpes simplex virus type 2 (HSV‐2) infection by reducing genital tissue expression of the cell‐cell adhesion molecule desmoglein‐1 (DSG‐1) and increasing genital mucosal permeability. Conversely, DMPA‐mediated increases in genital mucosal permeability and HSV‐2 susceptibility were eliminated in mice concomitantly administered exogenous oestrogen (E). To confirm and extend these findings, herein we used humanized mice to define effects of systemic DMPA and intravaginal (ivag) E administration on susceptibility to genital infection with cell‐associated HIV‐1.MethodsEffects of DMPA or an intravaginal (ivag) E cream on engraftment of NOD‐scid‐IL‐2Rgcnull (NSG) mice with human peripheral blood mononuclear cells (hPBMCs) were defined with flow cytometry. Confocal microscopy was used to evaluate effects of DMPA, DMPA and E cream, or DMPA and the pharmacologically active component of the cream on vaginal tissue DSG‐1 expression and genital mucosal permeability to low molecular weight (LMW) molecules and hPBMCs. In other studies, hPBMC‐engrafted NSG mice (hPBMC‐NSG) received DMPA or DMPA and ivag E cream before genital inoculation with 106 HIV‐1‐infected hPBMCs. Mice were euthanized 10 days after infection, and plasma HIV‐1 load quantified by qRT‐PCR and splenocytes used to detect HIV‐1 p24 antigen via immunohistochemistry and infectious virus via TZM‐bl luciferase assay.ResultsWhereas hPBMC engraftment was unaffected by DMPA or E treatment, mice administered DMPA and E (cream or the pharmacologically active cream component) displayed greater vaginal tissue expression of DSG‐1 protein and decreased vaginal mucosal permeability to LMW molecules and hPBMCs versus DMPA‐treated mice. DMPA‐treated hPBMC‐NSG mice were also uniformly susceptible to genital transmission of cell‐associated HIV‐1, while no animal concomitantly administered DMPA and E cream acquired systemic HIV‐1 infection.ConclusionExogenous E administration reduces susceptibility of DMPA‐treated humanized mice to genital HIV‐1 infection.

Dual-strain genital herpes simplex virus type 2 (HSV-2) infection in the US, Peru, and 8 countries in sub-Saharan Africa: A nested cross-sectional viral genotyping study.

BackgroundQuantitative estimation of the extent to which the immune system’s protective effect against one herpes simplex virus type 2 (HSV-2) infection protects against infection with additional HSV-2 strains is important for understanding the potential for HSV-2 vaccine development. Using viral genotyping, we estimated the prevalence of HSV-2 dual-strain infection and identified risk factors.Methods and findingsPeople with and without HIV infection participating in HSV-2 natural history studies (University of Washington Virology Research Clinic) and HIV prevention trials (HIV Prevention Trials Network 039 and Partners in Prevention HSV/HIV Transmission Study) in the US, Africa, and Peru with 2 genital specimens each containing ≥105 copies herpes simplex virus DNA/ml collected a median of 5 months apart (IQR: 2–11 months) were included. It is unlikely that 2 strains would be detected in the same sample simultaneously; therefore, 2 samples were required to detect dual-strain infection. We identified 85 HSV-2 SNPs that, in aggregate, could determine whether paired HSV-2 strains were the same or different with >90% probability. These SNPs were then used to create a customized high-throughput array-based genotyping assay. Participants were considered to be infected with more than 1 strain of HSV-2 if their samples differed by ≥5 SNPs between the paired samples, and dual-strain infection was confirmed using high-throughput sequencing (HTS). We genotyped pairs of genital specimens from 459 people; 213 (46%) were men, the median age was 34 years (IQR: 27–44), and 130 (28%) were HIV seropositive. Overall, 272 (59%) people were from the US, 59 (13%) were from Peru, and 128 (28%) were from 8 countries in Africa. Of the 459 people, 18 (3.9%) met the criteria for dual-strain infection. HTS and phylogenetic analysis of paired specimens confirmed shedding of 2 distinct HSV-2 strains collected at different times in 17 pairs, giving an estimated dual-strain infection prevalence of 3.7% (95% CI = 2.0%–5.4%). Paired samples with dual-strain infection differed by a median of 274 SNPs in the UL_US region (range 129–413). Matching our observed dual-strain infection frequency to simulated data of varying prevalences and allowing only 2 samples per person, we inferred the true prevalence of dual-strain infection to be 7%. In multivariable analysis, controlling for HIV status and continent of origin, people from Africa had a higher risk for dual-strain infection (risk ratio [RR] = 9.20, 95% CI = 2.05–41.32), as did people who were HIV seropositive (RR = 4.06, 95% CI = 1.42–11.56).ConclusionsHSV-2 dual-strain infection was detected in 3.7% of paired samples from individual participants, and was more frequent among people with HIV infection. Simulations suggest that the true prevalence of dual-strain infection is 7%. Our data indicate that naturally occurring immunity to HSV-2 may be protective against infection with a second strain. This study is limited by the inability to determine the timing of acquisition of the second strain.

Comparison of Acyclovir and Multistrain Lactobacillus brevis in Women with Recurrent Genital Herpes Infections: a Double-Blind, Randomized, Controlled Study

We performed a randomized double-blind controlled trial to compare the efficacy and safety of multistrain probiotic and acyclovir in women patients with recurrent genital herpes simplex virus type 2 (HSV-2) infections. Eighty-one patients enrolled in the study were being treated with multistrain Lactobacillus brevis one vaginal capsule every 12h and oral acyclovir 400mg twice daily for 6months. Of 53 patients who completed both treatment courses, no important differences were identified between acyclovir and probiotic for the primary and secondary efficacy endpoint, resolution of episode (hazard ratio, 0.60; 95% CI, 0.3429 to 1.0663; P=0.08), lesion healing time (hazard ratio, 0.57; 95% CI, 0.3034 to 1.0717, P=0.08), viral shedding (hazard ratio, 0.54; 95% CI, 0.3027 to 0.9750, P=0.04), and percentage of pain (hazard ratio, 0.48; 95% CI, 0.2708 to 0.8545, P=0.01). The median time to first and second recurrence after treatment were 43 and 121days in patients receiving acyclovir and 33 and 118days in patients receiving probiotic (HR 2.61; 95% CI, 1.4427 to 4.7546, P=0.001, and HR 0.62; 95% CI, 0.3500 to 1.1133, P=0.1, respectively). No clinically important effects happened during the probiotic treatment but some of adverse events reported in patients taking acyclovir. Easy availability, low cost, and no side effect of L. brevis are valuable properties of probiotic therapy compared with acyclovir. Therefore, we concluded that multistrain L. brevis could play an important role in suppression of recurrent genital herpes simplex virus infection.

Extracts of Equisetum giganteum L and Copaifera reticulate Ducke show strong antiviral activity against the sexually transmitted pathogen herpes simplex virus type 2

Ethnopharmacological relevanceEquisetum giganteum L and Copaifera reticulate Ducke have been traditionally used by women of the Tacana tribe in the Bolivian Amazonas for genital hygiene and for treatment of genital infection/inflammation. Aim of the studyTo assess the ability of extracts from Equisetum giganteum L and Copaifera reticulate Ducke to block genital viral infection by herpes simplex virus type 2. Materials and MethodsEquisetum giganteum L and Copaifera reticulate Ducke were collected from the Amazon region of La Paz, Bolivia. Extracts were prepared and screened for anti-viral activity against herpes simplex virus type 2 (HSV-2) using both in vitro and in in vivo models of infection. ResultsEquisetum giganteum L and Copaifera reticulate Ducke efficiently blocked HSV-2 infection of cell cultures without major cell cytotoxic effects. Extracts of Equisetum giganteum L and Copaifera reticulate Ducke could prevent HSV-2 disease development when administered together with virus in a mouse model of genital HSV-2 infection. In vitro analyses revealed that both plant extracts exerted their anti-HSV-2 effects by interfering with viral cell attachment and entry, but could not block viral replication post entry. ConclusionsThese studies show that extracts of Equisetum giganteum L and Copaifera reticulate Ducke have potent antiviral activities against HSV-2 comparable to those two previously identified plants, Croton lechleri Müll. Arg. and Uncaria tomentosa (Willd. ex Schult.) DC. These studies confirm that plants used by the Tacana tribe could be explored further for the development of novel topical antiviral microbicides.

Distinct Effects of the Cervicovaginal Microbiota and Herpes Simplex Type 2 Infection on Female Genital Tract Immunology.

Genital inflammation is a key determinant of human immunodeficiency virus (HIV) transmission, and may increase HIV-susceptible target cells and alter epithelial integrity. Several genital conditions that increase HIV risk are more prevalent in African, Caribbean, and other black (ACB) women, including bacterial vaginosis and herpes simplex virus type-2 (HSV-2) infection. Therefore, we assessed the impact of the genital microbiota on mucosal immunology in ACB women and microbiome-HSV-2 interactions. Cervicovaginal secretions and endocervical cells were collected by cytobrush and Instead Softcup, respectively. T cells and dendritic cells were assessed by flow cytometry, cytokines by multiplex enzyme-linked immunosorbent assay (ELISA), and the microbiota by 16S ribosomal ribonucleic acid gene sequencing. The cervicovaginal microbiota of 51 participants were composed of community state types (CSTs) showing diversity (20/51; 39%) or predominated by Lactobacillus iners (22/51; 42%), L. crispatus (7/51; 14%), or L. gasseri (2/51; 4%). High-diversity CSTs and specific bacterial phyla (Gardnerella vaginalis and Prevotella bivia) were strongly associated with cervicovaginal inflammatory cytokines, but not with altered endocervical immune cells. However, cervical CD4+ T-cell number was associated with HSV-2 infection and a distinct cytokine profile. This suggests that the genital microbiota and HSV-2 infection may influence HIV susceptibility through independent biological mechanisms.

First estimates of the global and regional incidence of neonatal herpes infection.

BackgroundNeonatal herpes is a rare but potentially devastating condition (60% fatality without treatment). Transmission usually occurs during delivery from mothers with herpes simplex virus type 1 (HSV-1) or HSV-2 genital infection. The global burden has never been quantified. We developed a novel methodology for burden estimation and present first WHO global and regional estimates of the annual number of neonatal herpes cases during 2010–2015.MethodsPrevious estimates of HSV-1 and HSV-2 prevalence and incidence in women aged 15–49 years were applied to 2010–2015 birth rates to estimate infections during pregnancy. Published risks of neonatal HSV transmission were then applied according to whether maternal infection was incident or prevalent with HSV-1 or HSV-2 to estimate neonatal herpes cases.FindingsGlobally the overall rate of neonatal herpes was estimated to be ~10 cases per 100,000 births, equivalent to a best-estimate of ~14,000 cases annually (HSV-1: ~4,000; HSV-2: ~10,000). We estimated that the most neonatal herpes cases occurred in Africa, due to high maternal HSV-2 infection and high birth rates. HSV-1 contributed more cases than HSV-2 in the Americas, Europe and Western Pacific. High rates of genital HSV-1 infection and moderate HSV-2 prevalence meant the Americas had the highest overall rate. However, our estimates are highly sensitive to the core assumptions, and considerable uncertainty exists for many settings given sparse underlying data.InterpretationThese neonatal herpes estimates mark the first attempt to quantify the global burden of this rare but serious condition. Better primary data collection on neonatal herpes is critically needed to reduce uncertainty and refine future estimates. This is particularly important in resource-poor settings where we may have underestimated cases. Nevertheless, these first estimates suggest development of new HSV prevention measures such as vaccines could have additional benefits beyond reducing genital ulcer disease and HSV-associated HIV transmission, through prevention of neonatal herpes.FundingWorld Health Organization